Accurate prediction of protein-ligand interactions by combining physical energy functions and graph-neural networks.

We introduce an advanced model for predicting protein-ligand interactions. Our approach combines the strengths of graph neural networks with physics-based scoring methods. Existing structure-based machine-learning models for protein-ligand binding prediction often fall short in practical virtual screening scenarios, hindered by the intricacies of binding poses, the chemical diversity of drug-like molecules, and the scarcity of crystallographic data for protein-ligand complexes.

Recent Trends in Drug Design and Discovery.

Introduction: Structure-based drug design is a wide area of identification of selective inhibitors of a target of interest. From the time of the availability of three dimensional structure of the drug targets, mostly the proteins, many computational methods had emerged to address the challenges associated with drug design process. Particularly, drug-likeness, druggability of the target protein, specificity, off-target binding, etc.

Identification of Potential Inhibitors for Targets Involved in Dengue Fever.

Lethality due to dengue infection is a global threat. Nearly 400 million people are affected every year, which approximately costs 500 million dollars for surveillance and vector control itself. Many investigations on the structure-function relationship of proteins expressed by the dengue virus are being made for more than a decade and had come up with many reports on small molecule drug discovery.

Role of disordered regions in transferring tyrosine to its cognate tRNA.

Aminoacyl tRNA synthetase (AARS) plays an important role in transferring each amino acid to its cognate tRNA. Specifically, tyrosyl tRNA synthetase (TyrRS) is involved in various functions including protection from DNA damage due to oxidative stress, protein synthesis and cell signaling and can be an attractive target for controlling the pathogens by early inhibition of translation. TyrRS has two disordered regions, which lack a stable 3D structure in solution, and are involved in tRNA synthetase catalysis and stability.

A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions.

Plant latex thrombin-like cysteine proteases alleviates bleeding by bypassing factor VIII in murine model.

Hemostasis is a tightly regulated process which maintains a fluid state of blood within the vasculature and provides thrombotic response upon tissue injury. Various scientific studies have implicated the role of plant latex proteases in hemostasis using in vitro experiments. However, in vivo models substantiate their role in hemostasis.

Identification of novel NAD(P)H dehydrogenase [quinone] 1 antagonist using computational approaches.

NAD(P)H: quinone oxidoreductase 1 (NQO1) inhibitors are proved as promising therapeutic agents against cancer. This study is to determine potent NAD(P)H-dependent NQO1 inhibitors with new scaffold. Pharmacophore-based three-dimensional (3D) QSAR model has been built based on 45 NQO1 inhibitors reported in the literature.

The non-enzymatic RAS effector RASSF7 inhibits oncogenic c-Myc function.

is a proto-oncogene controlling expression of multiple genes involved in cell growth and differentiation. Although the functional role of c-Myc as a transcriptional regulator has been intensively studied, targeting this protein in cancer remains a challenge. Here, we report a trimodal regulation of c-Myc function by the Ras effector, Ras-association domain family member 7 (RASSF7), a nonenzymatic protein modulating protein-protein interactions to regulate cell proliferation.

An iterative compound screening contest method for identifying target protein inhibitors using the tyrosine-protein kinase Yes.

We propose a new iterative screening contest method to identify target protein inhibitors. After conducting a compound screening contest in 2014, we report results acquired from a contest held in 2015 in this study. Our aims were to identify target enzyme inhibitors and to benchmark a variety of computer-aided drug discovery methods under identical experimental conditions.

Identification of type I and type II inhibitors of c-Yes kinase using in silico and experimental techniques.

c-Yes kinase is considered as one of the attractive targets for anti-cancer drug design. The DFG (Asp-Phe-Gly) motif present in most of the kinases will adopt active and inactive conformations, known as DFG-in and DFG-out and their inhibitors are classified into type I and type II, respectively. In the present study, two screening protocols were followed for identification of c-Yes kinase inhibitors.

Structure-function relationship of Chikungunya nsP2 protease: A comparative study with papain.

Chikungunya virus is a growing human pathogen transmitted by mosquito bite. It causes fever, chills, nausea, vomiting, joint pain, headache, and swelling in the joints. Its replication and propagation depend on the protease activity of the Chikungunya virus-nsP2 protein, which cleaves the nsP1234 polyprotein replication complex into individual functional units.

Celastrol modulates inflammation through inhibition of the catalytic activity of mediators of arachidonic acid pathway: Secretory phospholipase A group IIA, 5-lipoxygenase and cyclooxygenase-2.

Elevated production of arachidonic acid (AA)-derived pro-inflammatory eicosanoids due to the concerted action of secretory phospholipase A group IIA (sPLAIIA), 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) is a common feature of many inflammatory disorders. Hence, modulation of the bioactivity of these 3 enzymes is an important strategy to control inflammation. However, the failure of drugs specific for an individual enzyme (sPLAIIA-, 5-LOX- or COX-2) and the success of 5-LOX/COX-2 dual inhibitors in effectively controlling inflammation in clinical trials prompted us to evaluate a common inhibitor for sPLAIIA, 5-LOX and COX-2 enzymes.

Dimethyl ester of bilirubin exhibits anti-inflammatory activity through inhibition of secretory phospholipase A2, lipoxygenase and cyclooxygenase.

Overproduction of arachidonic acid (AA) mediated by secretory phospholipase A2 group IIA (sPLA2IIA) is a hallmark of many inflammatory disorders. AA is subsequently converted into pro-inflammatory eicosanoids through 5-lipoxygenase (5-LOX) and cyclooxygenase-1/2 (COX-1/2) activities. Hence, inhibition of sPLA2IIA, 5-LOX and COX-1/2 activities is critical in regulating inflammation.

Identification of potential inhibitors based on compound proposal contest: Tyrosine-protein kinase Yes as a target.

A search of broader range of chemical space is important for drug discovery. Different methods of computer-aided drug discovery (CADD) are known to propose compounds in different chemical spaces as hit molecules for the same target protein. This study aimed at using multiple CADD methods through open innovation to achieve a level of hit molecule diversity that is not achievable with any particular single method.

Progressive Hemorrhage and Myotoxicity Induced by Echis carinatus Venom in Murine Model: Neutralization by Inhibitor Cocktail of N,N,N',N'-Tetrakis (2-Pyridylmethyl) Ethane-1,2-Diamine and Silymarin.

Viperbite is often associated with severe local toxicity, including progressive hemorrhage and myotoxicity, persistent even after the administration of anti-snake venom (ASV). In the recent past, investigations have revealed the orchestrated actions of Zn2+ metalloproteases (Zn2+MPs), phospholipase A2s (PLA2s) and hyaluronidases (HYs) in the onset and progression of local toxicity from the bitten site. As a consequence, venom researchers and medical practitioners are in deliberate quest of potent molecules alongside ASV to tackle the brutal local manifestations induced by aforesaid venom toxins.

Structure based approach for understanding organism specific recognition of protein-RNA complexes.

Background: Protein-RNA interactions perform diverse functions within the cell. Understanding the recognition mechanism of protein-RNA complexes has been a challenging task in molecular and computational biology. In earlier works, the recognition mechanisms have been studied for a specific complex or using a set of non-redundant complexes.

Inhibitory potential of three zinc chelating agents against the proteolytic, hemorrhagic, and myotoxic activities of Echis carinatus venom.

Viperbites undeniably cause local manifestations such as hemorrhage and myotoxicity involving substantial degradation of extracellular matrix (ECM) at the site of envenomation and lead to progressive tissue damage and necrosis. The principle toxin responsible is attributed to snake venom metalloproteases (SVMPs). Treatment of such progressive tissue damage induced by SVMPs has become a challenging task for researchers and medical practitioners who are in quest of SVMPs inhibitors.

Identification of novel inhibitors of Daboia russelli phospholipase A2 using the combined pharmacophore modeling approach.

Crystal structures available for Daboia russelli venom PLA(2) confirm that it undergoes dimerization with asymmetry and hence difference in the conformation of active site of the two subunits. The active site of subunit A is open and that of subunit B is closed. Pharmacophore models were generated based on the interaction of different types of inhibitors with their preferred subsites in the active site of subunit A.